Inhibitors of platelet aggregation

Details Inhibitors of platelet aggregation Inhibitors of platelet aggregation

1996-10-31

1998-05-05

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

544254, C07H 1916, C07D48704, C07D40304, A61K 31505

Patent

active

057474966

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention is directed to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular in the prevention of platelet aggregation.


BACKGROUND AND PRIOR ART

A number of converging pathways lead to platelet aggregation. Whatever the initial stimulus, the final common event is a cross linking of platelets by binding of fibrinogen to a membrane binding site, glycoprotein IIb/IIIa (GPIIb/IIIa). The high anti-platelet efficacy of antibodies or antagonists for GPIIb/IIIa is explained by their interference with this final is common event. However, this efficacy may also explain the bleeding problems that have been observed with this class of agent.
Thrombin can produce platelet aggregation largely independently of other pathways but substantial quantities of thrombin are unlikely to be present without prior activation of platelets by other mechanisms. Thrombin inhibitors such as hirudin are highly effective anti-thrombotic agents, but again may produce excessive bleeding because they function as both anti-platelet and anti-coagulant agents (The TIMI 9a Investigators (1994), Circulation 90, pp. 1624-1630; The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators (1994) Circulation 90, pp. 1631-1637; Neuhaus K. L. et. al. (1994) Circulation 90, pp. 1638-1642).
Aspirin, which is known to have a beneficial effect on platelet aggregation, (see e.g. Antiplatelet Trialists' Collaboration (1994), Br. Med. J. 308, pp. 81-106; Antiplatelet Trialists' Collaboration (1994), Br. Med. J. 308, pp. 159-168) has no effect on aggregation produced by other sources of ADP, such as damaged cells or ADP released under conditions of turbulent blood flow. A pivotal role for ADP is supported by the fact that other agents, such as adrenaline and 5-hydroxytryptamine (5HT, serotonin) will only produce aggregation in the presence of ADP.
The inventors of the present invention started from the point that an antagonist of the effect of ADP on its platelet membrane receptor, the P.sub.2T -purinoceptor, would provide a more efficacious anti-thrombotic agent than aspirin but with less profound effects on bleeding than antagonists of the fibrinogen receptor.
U.S. Pat. No. 4,543,255 discloses carbocyclic analogues of 2-amino-6-substituted purine 2'-deoxyribofuranosides and of 2-amino-6-substituted-8-azapurine 2'-deoxyribofuranosides. The compounds of this prior art patent are disclosed as having inhibitory effect against herpes viruses.
WO 90/06671 discloses the use of carbocyclic analogues of various nucleosides for the treatment of Hepatitis B virus.
The problem underlying the present invention was to find novel compounds having improved P.sub.2T -receptor antagonist activity and with significant advantages with respect to known anti-platelet agents, such as improved efficacy, reduced side-effects, non-toxicity, and better selectivity for the P.sub.2T -receptor.
The problem mentioned above has now been solved by providing novel derivatives, as will be described below.


OUTLINE OF THE INVENTION

The novel compounds according to the present invention are defined by the general formula (I) ##STR2## wherein B is O or CH.sub.2 ; -C.sub.7 alkyl optionally substituted upon or within the alkyl chain by one or more of O, S, N or halogen; bond; C(O)NHCH(COOH)(CH.sub.2).sub.r COOH, or 5-tetrazolyl, wherein p, q and r is each and independently 1, 2 or 3;
The definition of alkyl is intended to include straight, branched, and cyclic alkyl chains, as well as saturated and unsaturated alkyl chains.
The O, S and N substituents may be substituents upon or within the alkyl chain. By this definition we mean C.sub.1 -C.sub.7 alkyl where one methylene within the chain may optionally be replaced by O, S or NH and in which the alkyl chain may be optionally substituted by one or more of OH, SH, NH.sub.2 or halogen.
Halogen includes chloro and fluoro.
Within the scope of the inve

REFERENCES:
patent: 5039689 (1991-08-01), Daluge
patent: 5506347 (1996-04-01), Erion et al.

Affiliated with

Also associated with

Rating

Inhibitors of platelet aggregation does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Inhibitors of platelet aggregation, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Inhibitors of platelet aggregation will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-54910